The following includes information that may be useful in understanding various aspects and embodiments of the present disclosure. It is not an admission that any of the information provided herein is prior art, or relevant, to the presently described or claimed inventions, or that any publication or document that is specifically or implicitly referenced is prior art.
The signal transducer and activator of transcription (Stat) family of proteins are cytoplasmic transcription factors with important roles in mediating responses to cytokines and growth factors, including promoting cell growth and differentiation, and inflammation and immune responses. Bromberg, Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development. Breast Cancer Res. 2:86-90 (2000); Darnell, Transcription factors as targets for cancer therapy, Nat. Rev. Cancer 2:740-749 (2002). Classically, the phosphorylation of Stats on a critical tyrosyl residue by growth factor receptor tyrosine kinases, or cytoplasmic tyrosine kinases, including Janus kinases or the Src family kinases, promotes the dimerization between two Stat monomers through a reciprocal phosphotyrosine-Src Homology (SH)2 domain interaction, translocation to the nucleus, and the binding to specific DNA-response elements in the promoters of target genes to regulate gene expression. By contrast, aberrantly-active Stat3, one of the Stat family members, has been implicated in many human tumors and represents an attractive target for drug discovery. The aberrant activation of Stat3 occurs in glioma, breast, prostate, ovarian, and many other human cancers, whereby it promotes malignant progression. Yu & Jove, The STATS of Cancer-New molecular targets come of age, Nat. Rev. Cancer 4:97-105 (2004); Yue & Turkson, Targeting STAT3 in cancer: how successful are we?, Expert Opin Investig Drugs. 18:45-56 (2009). Mechanisms by which constitutively-active Stat3 mediates tumorigenesis include dysregulation of gene expression that leads to uncontrolled growth and survival of tumor cells, enhanced tumor angiogenesis, and metastasis and the suppression of tumor immune surveillance. Yu & Jove (2004); Bromberg & Darnell, The role of STATs in transcriptional control and their impact on cellular function, Oncogene 19:2468-2473 (2000); Bowman et al., STATs in oncogenesis. Oncogene 19:2474-2488 (2000); Turkson J & Jove, STAT proteins: novel molecular targets for cancer drug discovery. Oncogene 19:6613-6626 (2000); Turkson, STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets 8:409-422 (2004); Wang et al., Regulation of the innate and adaptive immune responses by Stat-3 signaling in tumor cells. Nat Med 10:48-54 (2004).
Recent evidence also reveals the role of Stat3 in modulating mitochondrial functions and Stat3 crosstalk with other proteins, such as NF-κB, that promotes the malignant phenotype. Many human tumors harbor aberrantly-active signal transducer and activator of transcription (Stat)3 signaling, and studies in experimental models indicate tumor cells and tumors harboring constitutively-active Stat3 are responsive to Stat3 signaling modulators. See Gough et al., Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation. Science 324:1713 (2009); Yu et al., STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9:798-809 (2009); Grivennikov & Karin, Dangerous liaisons: STAT3 and NF-kB collaboration and crosstalk in cancer, Cytokine & Growth Factor Reviews 21:11-19 (2010).